What is the treatment for extensively drug-resistant (XDR) organisms with resistance to Carbapenem drugs, where Colistin is the last resort?

From the Guidelines

Colistin is indeed the last-resort antibiotic for treating extensively drug-resistant (XDR) organisms that have developed resistance to carbapenems. When carbapenem-resistant organisms like Klebsiella pneumoniae, Pseudomonas aeruginosa, or Acinetobacter baumannii are encountered, colistin (polymyxin E) or polymyxin B may be the only effective treatment options 1.

Key Considerations

• Typical colistin dosing is 9 MU of colistin methanesulfonate (CMS) initially followed by 4.5 MU CMS twice a day as the maintenance dose, as supported by pharmacodynamic studies in critically ill patients 1.
• Treatment duration typically ranges from 7-14 days depending on infection site and clinical response.
• Colistin should be used cautiously due to its nephrotoxicity and neurotoxicity, requiring close monitoring of renal function.
• In clinical practice, colistin is often combined with other antibiotics like meropenem, tigecycline, or fosfomycin for synergistic effects, even when in vitro testing shows resistance 1.

Alternative Options

• Newer agents like ceftazidime-avibactam, meropenem-vaborbactam, or cefiderocol may be alternatives for some carbapenem-resistant infections, but their effectiveness varies by resistance mechanism and should be guided by susceptibility testing 1.

Important Notes

• The optimal dosage of colistin in pediatric patients remains uncertain, and the current recommendations may be inadequate in cases where the MIC of the infecting pathogen is ≥ 1 mg/L or when the patient has augmented renal clearance or good renal function for their age 1.
• Colistin resistance is emerging globally, creating truly pan-resistant organisms, and its use should be guided by local epidemiology and antimicrobial susceptibility patterns 1.

From the FDA Drug Label

INDICATIONS AND USAGE Colistimethate for Injection, USP is indicated for the treatment of acute or chronic infections due to sensitive strains of certain gram-negative bacilli. Colistimethate for Injection, USP has proven clinically effective in treatment of infections due to the following gram-negative organisms: Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa

The use of Colistin as a last resort for XDR organisms that are resistant to Carbapenem drugs is implied by its effectiveness against certain gram-negative organisms, including Pseudomonas aeruginosa. However, the label does not explicitly state its use as a last resort for XDR organisms.

• The drug label does indicate that Colistin is effective against certain gram-negative bacteria.
• It is important to note that the development of drug-resistant bacteria should be considered when using Colistin, and it should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria 2.

From the Research

XDR Organisms' Resistance to Carbapenem Drugs

• XDR organisms, including Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, have developed resistance to carbapenem drugs, making treatment challenging 3.
• Colistin is considered a last-resort antibiotic for the treatment of XDR Gram-negative infections, including those caused by carbapenemase-producing bacteria 3, 4.

Mechanism of Action and Resistance

• Colistin works by disrupting the bacterial membrane, causing lethality, but its use is limited due to nephrotoxicity and neurotoxicity 5.
• Resistance to colistin arises primarily through the modification of lipopolysaccharides (LPS) in the outer membrane, regulated by bacterial two-component signal transduction (TCS) systems 5.

Treatment Outcomes and Adverse Effects

• Studies have shown that colistin is efficacious in clearing bacteremia, even in patients with impaired renal function, with minimal and reversible adverse effects 4.
• However, the use of colistin is not without risks, and factors such as inappropriate empirical antibiotics and acute renal failure are associated with increased mortality 4.

Emerging Resistance and Future Directions

• Emerging resistance to last-line antimicrobial agents, including fosfomycin, colistin, and ceftazidime-avibactam, is a significant concern, highlighting the need for effective national and international surveillance systems 6.
• The development of new antibiotics and alternative treatment strategies, such as targeting TCS signaling mechanisms, is crucial to combat XDR Gram-negative infections 7, 5.